Neurologic dysfunction frequently accompanies HIV infection of children. The incidence of neurologic abnormalities is higher in HIV-1 infected children than in adults and the patterns of neurologic disease differ from those observed in adult AIDS patients. The reasons for these differences are obscure. A likely explanation is the immaturity of the hosts immune and nervous systems at the time of infection. This would be particularly true for infants infected in utero. To examine these issues we performed in utero inoculation (intraperitoneal) of rhesus fetuses with 1 adult animal infectious dose of SIVmac251 at gestational day (GD) 65 (n = 8), 110 (n = 4) and 130 (n = 2) and then collected the fetuses by cesarean section at one or more of the following time points GD 80, 100, 130, and 145. Age matched, mock inoculated fetuses were also collected as controls. The time points for inoculation correspond to periods of initial development of the immune system and early development of the cerebral cortical plate (GD65) through later stages (GD130) when immune competence and the brain are more fully developed. Brain from all of these animals was examined by routine histology, immunohistochemistry and in situ hybridization to localize viral and cellular proteins and viral nucleic acid. Histologically we found scattered glial nodules, spongiosis, and mineralization in the basal ganglia and deep white matter in 4 of the animals. These same animals as well as animals without histologic lesions had viral nucleic acid and antigen in the stroma of the choroid plexus, meninges, external germinative layer of the cerebellum, and in columns of cells along radial glia in the cortical plate. In contrast to juvenile and adult macaques, very few SIV+ perivascular mononuclear cells were present. These difference in viral distribution in the CNS may explain many